Effect of the new dual orexin receptor antagonist daridorexant on nighttime respiratory function and sleep in patients with mild and moderate obstructive sleep apnea

Abstract

In this randomized, double-blind, placebo-controlled, two-period crossover study, the effect of the dual orexin receptor antagonist daridorexant was evaluated on nighttime respiratory function and sleep in 28 patients with mild and moderate obstructive sleep apnea (OSA). In each period, 50 mg daridorexant or placebo was administered every evening for 5 days. The primary endpoint was apnea/hypopnea index (AHI) during total sleep time (TST) after the last dosing. Other endpoints included peripheral oxygen saturation (SpO2), sleep duration, latency to persistent sleep (LPS), wake after sleep onset (WASO), and sleep efficiency index (SEI). Pharmacokinetics, safety, and tolerability were also assessed. The mean treatment difference for AHI during TST (i.e. daridorexant − placebo) after the last dosing was 0.74 events/hour (90% confidence interval [CI]: –1.43, 2.92). The corresponding treatment difference for SpO2 during TST was 0.16% [90% CI: –0.21, 0.53]. Overall, there was no clinically relevant effect of daridorexant on AHI or SpO2-related data after single and repeated dosing irrespective of sleep phase (i.e. rapid eye movement [REM] vs non-REM). Moreover, after single and repeated dosing, daridorexant prolonged TST by 39.6 minutes (90% CI: 16.9, 62.3) and 38.8 minutes (19.7, 57.9), respectively, compared with placebo and favorably modulated other sleep-related endpoints (i.e. increased SEI, decreased WASO, and shortened LPS). It attained expected plasma concentrations and was well tolerated in patients with mild and moderate OSA. These results indicate that single and repeated doses of 50 mg daridorexant do not impair nighttime respiratory function and improve sleep in patients with mild and moderate OSA. Clinical Trial Registration ClinicalTrials.gov NCT03765294. A study to investigate the effects of ACT-541468 on nighttime respiratory function in patients with mild to moderate obstructive sleep apnea. https://clinicaltrials.gov/ct2/show/ NCT03765294.

Daridorexant: First Approval

“…The effects of a 50 mg nightly dose of daridorexant on respiratory function have been investigated in placebo-controlled crossover studies in patients with mild-to-moderate obstructive sleep apnoea (OSA) [NCT03765294] and moderate chronic obstructive pulmonary disease (COPD) [NCT03646864]. Administration of daridorexant to patients (n = 25) with mild-to-moderate OSA (5-30 apnoea-hypopnoea events/h) not requiring continuous positive airway pressure (CPAP) for 5 days was associated with a 0.74 (90% CI -1.43 to 2.92) events/h mean treatment difference in apnoea/hypopnoea index during total sleep time (TST) compared to placebo [13]. Administration of daridorexant to patients (n = 26) with moderate COPD was not associated with a significant change in peripheral oxygen saturation during TST compared to placebo (mean treatment difference 0.18% (90% CI − 0.21 to 0.57) [14].…”

Effect of the novel dual orexin receptor antagonist daridorexant on night‐time respiratory function and sleep in patients with moderate chronic obstructive pulmonary disease

“…Notably, the slight increase in the AHI was not accompanied by a decrease in mean nocturnal SpO 2 , further confirming the lack of clinical relevance. In patients with mild‐to‐moderate OSA, daridorexant also had no clinically meaningful effect on night‐time respiratory function in a previous clinical study (Boof et al, 2020).…”

“…Nocturnal desaturation is potentiated in patients with overlap syndrome compared to patients with either disease alone (McNicholas, 2009; Shawon et al., 2017). In patients with OSA, the AHI is used as the primary endpoint with an increase of ≥5 events/hr defined as clinically meaningful (Boof et al, 2020; Cheng et al., 2020; Sun et al., 2016). After the first and last dosing with daridorexant, the AHI was slightly increased compared to placebo, but not to a clinically meaningful extent as a change of AHI by 2 events/hr is within the normal night‐to‐night variability (Fietze et al., 2020).…”

Daridorexant: A New Dual Orexin Receptor Antagonist for Insomnia

“…18 Daridorexant does not affect nighttime respiratory function in subjects with mild or moderate obstructive sleep apnea or moderate chronic obstructive pulmonary disease (COPD); however, daridorexant was not studied in patients with severe obstructive sleep apnea or COPD. 19,20 Daridorexant is a federally controlled substance due to its risk for misuse and abuse. 5 Daridorexant does not have a history of diversion from clinical trials; however, it did show dose-related drug-liking in human abuse potential (HAP) studies.…”